ethyl 3,4-dihydro-2H-1,4-benzoxazine-2-carboxylate

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Acetyl chloride (23 □L, 0.33 mmol) was added to a solution of (±)-ethyl 3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate (Example 3a, 55 mg, 0.27 mmol), DMAP (1.6 mg, 0.013 mmol), and Hunig's base (63 □L, 0.36 mmol) in dichloromethane (2 mL). The solution was stirred at 25° C. for 24 h, then the reaction mixture was diluted with dichloromethane (60 mL) and the mixture was extracted with 0.1 M sodium carbonate (7 mL) and half-saturated brine (7 mL). The organic layer was dried over sodium sulfate and concentrated. Purification of the product by flash column chromatography (40% EtOAc/hexane) afforded the title compound (46 mg, 0.18 mmol). MS m/z: 250 (M+1). the mixture was extracted with 0.1 M sodium carbonate (7 mL) and half-saturated brine (7 mL) The organic layer was dried over sodium sulfate concentrated Purification of the product by flash column chromatography (40% EtOAc/hexane)

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Acetyl chloride (23 □L, 0.33 mmol) was added to a solution of (±)-ethyl 3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate (Example 3a, 55 mg, 0.27 mmol), DMAP (1.6 mg, 0.013 mmol), and Hunig's base (63 □L, 0.36 mmol) in dichloromethane (2 mL). The solution was stirred at 25° C. for 24 h, then the reaction mixture was diluted with dichloromethane (60 mL) and the mixture was extracted with 0.1 M sodium carbonate (7 mL) and half-saturated brine (7 mL). The organic layer was dried over sodium sulfate and concentrated. Purification of the product by flash column chromatography (40% EtOAc/hexane) afforded the title compound (46 mg, 0.18 mmol). MS m/z: 250 (M+1). the mixture was extracted with 0.1 M sodium carbonate (7 mL) and half-saturated brine (7 mL) The organic layer was dried over sodium sulfate concentrated Purification of the product by flash column chromatography (40% EtOAc/hexane)

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a sealable vessel, potassium carbonate (56 mg, 0.41 mmol) was added to a solution of (±)-ethyl 3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate (60 mg, 0.29 mmol) and iodomethane (22 □L, 0.35 mmol) in acetone (2 mL). The vessel was sealed and the reaction mixture was stirred at 60° C. for 24 h. The mixture was cooled to ambient temperature, diluted with dichloromethane (60 mL), and the organic layer was extracted with water (10 mL) and half-saturated brine (10 mL). The organic layer was dried over sodium sulfate and concentrated. Purification of the concentrate by flash column chromatography (5% to 10% EtOAc/hexane) afforded the title compound (43 mg, 0.19 mmol). MS m/z: 222 (M+1). The vessel was sealed The mixture was cooled to ambient temperature the organic layer was extracted with water (10 mL) and half-saturated brine (10 mL) The organic layer was dried over sodium sulfate concentrated Purification of the concentrate by flash column chromatography (5% to 10% EtOAc/hexane)

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a sealable vessel, potassium carbonate (56 mg, 0.41 mmol) was added to a solution of (±)-ethyl 3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate (60 mg, 0.29 mmol) and iodomethane (22 □L, 0.35 mmol) in acetone (2 mL). The vessel was sealed and the reaction mixture was stirred at 60° C. for 24 h. The mixture was cooled to ambient temperature, diluted with dichloromethane (60 mL), and the organic layer was extracted with water (10 mL) and half-saturated brine (10 mL). The organic layer was dried over sodium sulfate and concentrated. Purification of the concentrate by flash column chromatography (5% to 10% EtOAc/hexane) afforded the title compound (43 mg, 0.19 mmol). MS m/z: 222 (M+1). The vessel was sealed The mixture was cooled to ambient temperature the organic layer was extracted with water (10 mL) and half-saturated brine (10 mL) The organic layer was dried over sodium sulfate concentrated Purification of the concentrate by flash column chromatography (5% to 10% EtOAc/hexane)

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a sealable tube, tris(dibenzylideneacetone) dipalladium (0) (5.2 mg, 0.0056 mmol), (S)-BINAP (10.7 mg, 0.017 mmol), cesium carbonate (132 mg, 0.41 mmol), 2-bromopyridine (33 □L, 0.35 mmol), and ethyl 3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate (Example 3a, 60 mg, 0.29 mmol) were dissolved in dioxane (2 mL). The reaction vessel was sealed and the suspension was heated at 100° C. for 20 h. The reaction mixture was cooled to ambient temperature, diluted with water (15 mL), and the product was extracted with dichloromethane (3×20 mL). The organic fractions were dried over sodium sulfate and concentrated. Purification of the product by flash column chromatography (15% to 25% EtOAc/hexane) afforded the title compound (46 mg, 0.16 mmol). MS m/z: 285 (M+1). The reaction vessel was sealed The reaction mixture was cooled to ambient temperature the product was extracted with dichloromethane (3×20 mL) The organic fractions were dried over sodium sulfate concentrated Purification of the product by flash column chromatography (15% to 25% EtOAc/hexane)

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a sealable tube, tris(dibenzylideneacetone) dipalladium (0) (5.2 mg, 0.0056 mmol), (S)-BINAP (10.7 mg, 0.017 mmol), cesium carbonate (132 mg, 0.41 mmol), 2-bromopyridine (33 □L, 0.35 mmol), and ethyl 3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate (Example 3a, 60 mg, 0.29 mmol) were dissolved in dioxane (2 mL). The reaction vessel was sealed and the suspension was heated at 100° C. for 20 h. The reaction mixture was cooled to ambient temperature, diluted with water (15 mL), and the product was extracted with dichloromethane (3×20 mL). The organic fractions were dried over sodium sulfate and concentrated. Purification of the product by flash column chromatography (15% to 25% EtOAc/hexane) afforded the title compound (46 mg, 0.16 mmol). MS m/z: 285 (M+1). The reaction vessel was sealed The reaction mixture was cooled to ambient temperature the product was extracted with dichloromethane (3×20 mL) The organic fractions were dried over sodium sulfate concentrated Purification of the product by flash column chromatography (15% to 25% EtOAc/hexane)

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Tris(dibenzylideneacetone)dipalladium (0) (4.3 mg, 0.0046 mmol), xantphos (8.2 mg, 0.014 mmol), and bromobenzene (40 □L, 0.381 mmol) were added to a solution of (±)-ethyl 3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate (65 mg, 0.31 mmol) in dioxane (2.5 mL). The solids were allowed to dissolve, and cesium carbonate (143 mg, 0.44 mmol) was added, and the suspension was stirred at 100° C. for 24 h. The mixture was cooled to ambient temperature, diluted with water (20 mL), and the product was extracted with 67% EtOAc/hexane (3×25 mL). The organic layers were combined, dried over sodium sulfate, and concentrated. Purification of the crude concentrate by flash column chromatography using 15% EtOAc/hexane afforded the title compound. MS m/z: 284 (M+1). to dissolve The mixture was cooled to ambient temperature the product was extracted with 67% EtOAc/hexane (3×25 mL) dried over sodium sulfate concentrated Purification of the crude concentrate by flash column chromatography

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Tris(dibenzylideneacetone)dipalladium (0) (4.3 mg, 0.0046 mmol), xantphos (8.2 mg, 0.014 mmol), and bromobenzene (40 □L, 0.381 mmol) were added to a solution of (±)-ethyl 3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate (65 mg, 0.31 mmol) in dioxane (2.5 mL). The solids were allowed to dissolve, and cesium carbonate (143 mg, 0.44 mmol) was added, and the suspension was stirred at 100° C. for 24 h. The mixture was cooled to ambient temperature, diluted with water (20 mL), and the product was extracted with 67% EtOAc/hexane (3×25 mL). The organic layers were combined, dried over sodium sulfate, and concentrated. Purification of the crude concentrate by flash column chromatography using 15% EtOAc/hexane afforded the title compound. MS m/z: 284 (M+1). to dissolve The mixture was cooled to ambient temperature the product was extracted with 67% EtOAc/hexane (3×25 mL) dried over sodium sulfate concentrated Purification of the crude concentrate by flash column chromatography